1. Field of the Invention
This invention relates to a pharmaceutical composition for the treatment of radiation hazards, in which SCF (stem cell factor) protein, IL-3 (interleukin-3) protein, GM-CSF (granulocyte macrophage colony stimulating factor) protein and IL-6 (interleukin-6) protein are comprised in combination as the active components.
This invention also relates to a method for the treatment of patients with radiation hazards using such a pharmaceutical composition.
2. Prior Art
Radiations, e.g. .alpha.-, .beta.- and .gamma.-rays released from radioactive materials, or X-ray, proton beam, neutron beam and electron beam which are artificially produced, cause the abnormality of the cell division system in living cells thus resulting in lack of the ability of the cell growth. Cells are destroyed normally when exposed to an excess dose of the radiations. It is assumed that disorders in the central nervous system occur in a dose of 50 Gy or more, intestinal disorders in a dose of 10 Gy or more, and hematopoietic disorders in a dose of from 6 Gy to 10 Gy, thereby leading to the death of living bodies ("Gy" is a unit of absorbed radiation dose). Thus, the hematopoietic tissues or cells, particularly bone marrow cells, have the highest radiation sensitivity in the living body. The term "bone marrow cells" as used herein is referred to cells at various differentiation stages which exist in the bone marrow, such as crythrocytes, neutrophils, eosinophils, basophils, monocytes and thrombocytes.
When exposed to a radiation, the numbers of peripheral blood cells, especially leukocytes and thrombocytes, decrease sharply affecting the living body's survival. Hence, the bone marrow transplantation is an effective curative treatment when the living body is exposed to a radiation of 6 Gy or more. In the bone marrow transplantation, the human leucocyte antigen (HLA) in the bone marrow of a donor and that of a recipient should coincide with each other, since the incompatibility of HLA causes a graft-versus-host disease (GVED). In the present situation, however, it is extremely difficult to obtain bone marrow cells having compatibility of HLA.
With the popularization of nuclear power generation and the development of atomic industries such as nuclear fuel treatment, the possibility of causing exposure accidents has now been increasing among people engaged in radiation-operating works. Also, by the accident at the nuclear plant in Chernovuiri, inhabitants, as well as for example domestic animals, in the neighboring region have undergone serious influences. When exposed to such strong radiations, however, there are no available drugs which can protect from the radiation hazards effectively.
Current therapies for the treatment of malignancies are associated with significant damages to the hematopoietic system since radiation therapy do not discriminate between malignant cells and normal cells. This results in cessation of blood cell production leading to pancytopenia. Lymphocytes are depressed most rapidly followed by leukocytes, thrombocytes and erythrocytes. Then clinical problems such as decreased resistance to infection, anemia, and bleeding occur. At the same time, medical workers such as X-ray technicians, physicians have a chance to be irradiated while they work, these problems are not only for malignant patients but also for medical workers.
In recent years, several methods have been proposed which use certain substances that have a surviving effect from lethal cause, such as IL-1 (interleukin-1) (Neta, R. et al., J. Immunol., vol.136, p.2483, 1986; and Aihara, K. et al., U.S. Pat. No. 5,120,534), G-CSF (granulocyte colony stimulating factor) (Tanigawa, S. et al., Blood, vol.76, p.445, 1990), SCF (stem cell factor, Zsebo, K. M. et al., WO91/05795), ammonium trichloro(dioxoethylene-O,O')tellurate known as an immunomodulator (Kalechman, Y. et al., J. Immunol., vol.145, p.1512, 1990; JP-A-2-200630), nonapeptide known as a serum thymic factor (JP-A-2-36126), a cimetidine-copper complex (JP-A-1-153640), and 2-phenyl-1,2-benzoisoselenazol-3(2H)-one (JP-A-1-135718). However, there are in fact still great demands on radiation protecting agents which have superior effects to the prior art agents.
In this connection, several treatment methods have also been proposed in which combinations of growth factors are used to attain their synergistic effect: for example, combination of GM-CSF, G-CSF, IL-6, IL-5 (interleukin-5) and IL-3 for production of megakaryocytes (WO 91/07988); combination of MMF (megakaryocyte maturating factor), SCF, G-CSF, IL-3, Meg-CSF (megakaryocyte colony stimulating factor) and Epo (erythropoietin) (WO 92/06712) or combination of IL-7 (interleukin-7), IL-1.alpha. (interleukin-1.alpha.), IL-1.beta., IL-3, IL-4 (interleukin-4), IL-6, Epo, GM-CSF and G-CSF (WO 90/09194) for treatment of thrombocytopenia; and combination of IL-4, GM-CSF, G-CSF, IL-1, IL-2 (interleukin-2), IL-3, IL-5, IL-6 and IFN (interferon)-.alpha. (EP/410750) or combination of BCDF (B cell differentiation factor), IL-1, IL-3, IL-4, G-CSF, GM-CSF and M-CSF (macrophage colony stimulating factor) (EP 350641) or combination of IL-1.alpha., TNF (tumor necrosis factor) .alpha., G-CSF and GM-CSF (Neta, R. et al., J. Immunol., vol.140, p.108, 1988) for radiation protection.
We have studied on the most efficient radiation protection among various combinations of growth factors and found that the specific combination of SCF, IL-3, GM-CSF and IL-6 shows a markedly high radiation protection after exposure to radiations.